CN113173911A - Synthesis method of imidacloprid metabolite 5-hydroxy imidacloprid - Google Patents
Synthesis method of imidacloprid metabolite 5-hydroxy imidacloprid Download PDFInfo
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- CN113173911A CN113173911A CN202110433568.2A CN202110433568A CN113173911A CN 113173911 A CN113173911 A CN 113173911A CN 202110433568 A CN202110433568 A CN 202110433568A CN 113173911 A CN113173911 A CN 113173911A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
The invention discloses a method for synthesizing imidacloprid metabolite 5-hydroxy imidacloprid, and belongs to the field of medicine synthesis. The synthesis method provided by the application takes 5-hydroxy methyl nicotinate as a raw material, and realizes the synthesis of imidacloprid metabolite 5-hydroxy imidacloprid for the first time through six-step reaction.
Description
Technical Field
The invention belongs to a medicine synthesis technology, and particularly relates to a synthesis method of imidacloprid metabolite 5-hydroxy imidacloprid.
Background
Imidacloprid is a nitromethylene systemic insecticide, is an action body of a nicotine acetylcholine receptor, belongs to chloronicotinyl insecticides, is also called neonicotinyl insecticides, has a chemical formula of C9H10ClN5O2, and has a structural formula as follows:
it disables chemical signaling by interfering with the pest motor nervous system, without cross-resistance problems. Imidacloprid is a new generation of chloro nicotine pesticide, has broad spectrum, high efficiency, low toxicity and low residue, is not easy to generate resistance by pests, and has multiple effects of contact poisoning, stomach toxicity, systemic absorption and the like. After the pests contact the pesticide, normal conduction of central nerves is blocked, so that the pests die in paralysis. The product has good quick action, has higher control effect 1 day after being applied, and has a residual period of about 25 days. The pesticide effect and the temperature are positively correlated, the temperature is high, and the insecticidal effect is good. The insecticidal composition is mainly used for preventing and controlling piercing-sucking mouthpart pests and resistant strains thereof.
According to the published information report, the 5-hydroxy imidacloprid is a metabolite which is found in the bee body, so that the synthesis of the 5-hydroxy imidacloprid can provide important support for the research of imidacloprid, provide samples for the research and prevention of environmental impact and harm which may be caused after the imidacloprid is used, and have important application value. The synthesis method of 5-hydroxy imidacloprid provided by the invention has not been reported at present.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the prior art, the application provides a synthetic method of imidacloprid metabolite 5-hydroxy imidacloprid.
The technical scheme is as follows: the synthetic method of the imidacloprid metabolite 5-hydroxy imidacloprid is disclosed by the application, and the synthetic route is as follows:
the method specifically comprises the following steps:
(1) dissolving a compound I, namely 5-hydroxy methyl nicotinate in a solvent, and reacting with a chlorinating reagent to obtain a compound II;
(2) dissolving the compound II obtained in the step (1) in a solvent, and reacting with alkali and alkyl halide to obtain a compound III;
wherein, in the compound III, R is alkyl substituent such as methyl, benzyl, allyl or hydrogen, when R is hydrogen, namely, the compound II is directly used for the next reaction without the one-step reaction, and belongs to the compound III in the form of the compound III for the convenience of expression;
(3) dissolving the compound III obtained in the step (2) in a solvent, adding a reducing agent, and reacting to obtain a compound IV;
(4) dissolving the compound IV obtained in the step (3) in a solvent, and halogenating with a halogenating reagent to obtain a compound V;
wherein in the compound V, X is chlorine, bromine or iodine;
(5) dissolving the compound V obtained in the step (4) in a solvent, and reacting the compound V with a compound VI under an alkaline condition to obtain a compound VII;
note: when R is hydrogen, the compound VII is 5-hydroxy imidacloprid without the step (6);
(6) dissolving the compound VII obtained in the step (5) in an organic solvent, and reacting with a deprotection reagent to obtain a compound VIII, namely 5-hydroxy imidacloprid;
in the step (1), the solvent N, N-dimethylformamide, water, dioxane or dichloroethane is adopted, and the volume ratio of the solvent to the compound I is 5-30: 1. further preferably, the solvent is water, and the volume ratio is 9.35: 1.
in the step (1), the chlorination reagent is chlorine, N-chlorosuccinimide or sodium hypochlorite, and the molar ratio of the chlorination reagent to the compound I is 1-4: 1. further preferably, the chlorinating agent is sodium hypochlorite, and the molar ratio is 1: 1.
in the step (1), the reaction temperature is-10 ℃ to 100 ℃, and the reaction time is 0.5 to 16 hours. More preferably, the reaction is carried out at 10 ℃ for 2 hours.
In the step (2), R in the compound III is an alkyl substituent such as methyl, benzyl, allyl or hydrogen, preferably benzyl.
In the step (2), the solvent is acetone, acetonitrile, N-dimethylformamide or N, N-dimethylacetamide, and the volume ratio of the solvent to the compound II is 10-100: 1. further preferably, the organic solvent is acetonitrile, and the volume ratio is 25: 1.
in the step (2), the alkali is potassium carbonate, cesium carbonate, triethylamine or sodium hydroxide, and the molar ratio of the reagent to the compound II is 1-6: 1. further preferably, the organic solvent is cesium carbonate, and the molar ratio is 1.5: 1.
in the step (2), the alkyl halide is methyl iodide, benzyl bromide, benzyl chloride or allyl bromide, and the molar ratio of the alkyl halide to the compound II is 1-3: 1. further preferably, the organic solvent is benzyl chloride, and the molar ratio is 1.1: 1.
in the step (2), the reaction temperature is-20 ℃ to 150 ℃, and the reaction time is 1 to 16 hours. More preferably, 60 ℃ is selected and the reaction is carried out for 8 hours.
In the step (3), the solvent is tetrahydrofuran, toluene, methanol or diethyl ether, and the volume ratio of the solvent to the compound III is 5-80: 1. further preferably, the organic solvent is diethyl ether, and the volume ratio is 40: 1.
in the step (3), the reducing agent is lithium borohydride, sodium borohydride, lithium aluminum hydride or diisobutyl aluminum hydride, and the molar ratio of the reagent to the compound III is 0.5-5: 1. further preferably, the reducing agent is lithium borohydride, and the molar ratio is 1: 1.
in the step (3), the reaction temperature is-20 ℃ to 40 ℃, and the reaction time is 0.5 to 18 hours. More preferably, the reaction is carried out at 25 ℃ for 16 hours.
In the step (4), in the compound V, X is chlorine, bromine or iodine, preferably bromine.
In the step (4), the solvent is chloroform, dioxane, tetrahydrofuran or dichloromethane, and the volume ratio of the solvent to the compound IV is 5-50: 1. further preferably, the organic solvent is tetrahydrofuran, and the volume ratio is 15: 1.
in the step (4), the halogenating reagent is thionyl chloride, N-bromosuccinimide, phosphorus tribromide or iodine, and the mass ratio or molar ratio of the reagent to the compound IV is 0.1-5: 1. further preferably, the halogenating agent is phosphorus tribromide, and the molar ratio is 1.5: 1.
in the step (4), the reaction temperature is-20 ℃ to 75 ℃, and the reaction time is 1 to 48 hours. More preferably, the reaction is carried out at 0 ℃ for 4 hours.
In the step (5), the molar ratio of the compound VI to the compound V is 0.7-2.2: 1. as a more preferred embodiment, the bromide (X ═ Br) is selected and the molar ratio is 1.2: 1.
in the step (5), the solvent is N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide or N, N-dimethylacetamide, and the volume ratio of the solvent to the compound V is 5-50: 1. further preferably, the organic solvent is N, N-dimethylformamide, and the volume ratio is 8: 1.
in the step (5), the reaction reagent is potassium carbonate, cesium carbonate, sodium bicarbonate or triethylamine, and the molar ratio of the reagent to the compound V is 1-4: 1. further preferably, the reaction reagent is triethylamine, and the molar ratio is 2: 1.
in the step (5), the reaction temperature is-20 ℃ to 120 ℃, and the reaction time is 1 to 72 hours. More preferably, 80 ℃ is selected and the reaction is carried out for 24 hours.
In the step (6), the solvent is dichloromethane, dichloroethane, dioxane or toluene, and the volume ratio of the organic solvent to the compound VII is 5-50: 1. further preferably, the organic solvent is dichloromethane, and the volume ratio is 30: 1.
in the step (6), the deprotection reagent is boron trichloride, boron tribromide, aluminum trichloride or palladium tetratriphenylphosphine, and the molar ratio of the reagent to the compound VII is 0.1-5: 1. further preferably, the organic solvent is boron trichloride, and the molar ratio is 3: 1.
in the step (6), the reaction temperature is-78-120 ℃, and the reaction time is 1-36 hours. More preferably, the reaction is carried out at 20 ℃ for 16 hours.
Has the advantages that: the synthetic method of the imidacloprid metabolite 5-hydroxy imidacloprid has reasonable process design and strong operability, wherein the reaction route and the optimal reaction conditions of each reaction step are obtained by a large number of experimental screens. The purity of the 5-hydroxy imidacloprid prepared by the method provided by the application is as high as more than 99%, and the yield is high. The imidacloprid metabolite 5-hydroxy imidacloprid synthesized by the method can be used for researches on pharmacokinetics, raw material medicine impurity identification, environmental control, protection and the like, and has important application value for impurity identification, metabolic mechanism, new medicine research design, environmental protection and the like of imidacloprid.
Drawings
FIG. 1 is an IR spectrum of 5-hydroxypicolin VIII obtained in example 1;
FIG. 2 is an NMR spectrum of 5-hydroxypicolin VIII obtained in example 1;
FIG. 3 is an HPLC chromatogram of 5-hydroxypicolin VIII obtained in example 1;
FIG. 4 is the MS spectrum of 5-hydroxy imidacloprid VIII prepared in example 1.
Detailed Description
The present application will be described in detail with reference to specific examples.
Example 1
The synthesis method of the 5-hydroxy imidacloprid comprises the following steps:
(1) synthesis of intermediate II
The reaction process is as follows:
after 7 g of methyl 5-hydroxynicotinate was placed in a 1L round-bottom flask and cooled to 10 ℃ and 66 ml of sodium hypochlorite solution (5.2% available chlorine), 21 ml of 4 mol/L hydrochloric acid was added thereto and stirred at this temperature for 1 hour after stirring at this temperature. Dichloromethane was added for extraction three times, 100 ml each time, the combined organic phases were dried over anhydrous sodium sulfate, then concentrated and column chromatographed to give 5.27 g of an oil, intermediate ii, in 61.4% yield.
(2) Synthesis of intermediate IIIa
The reaction process is as follows:
dissolving 5.2 g of the intermediate II in 130 ml of acetonitrile, adding 13.55 g of cesium carbonate at room temperature, stirring for 20 minutes, adding 3.86 g of benzyl chloride, heating to 60 ℃, reacting for 8 hours, cooling to 25 ℃, carrying out suction filtration on the reaction solution, concentrating the filtrate, and purifying by column chromatography to obtain 6.82 g of oily matter, namely the intermediate IIIa, with the yield of 88.6%.
(3) Synthesis of intermediate IVa
The reaction process is as follows:
6.8 g of intermediate IIIa are dissolved in 272 ml of diethyl ether, 0.53 g of lithium borohydride are added slowly in portions in ice bath and the reaction is then gradually brought back to room temperature for 16 hours at 25 ℃. The reaction solution was again quenched with 1 mol/l dilute hydrochloric acid in an ice bath, the organic phase was washed with 300 ml of saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain 5.78 g of an oily substance, i.e., intermediate iva, with a yield of 94.5%.
(4) Synthesis of intermediate Va
The reaction process is as follows:
5.7 g of the intermediate IVa were dissolved in 85.5 ml of tetrahydrofuran, 9.27 g of phosphorus tribromide were added at 0 ℃ and the reaction was continued for 4 hours. The reaction was quenched with saturated sodium bicarbonate on an ice bath, adjusted to pH 8-9, then extracted three times with ethyl acetate, 75 ml each time, dried over anhydrous sodium sulfate, and concentrated to give 7.10 g of an oil, intermediate va, in 99.5% yield.
(5) Synthesis of intermediate VIIa
The reaction process is as follows:
7.1 g of the intermediate Va is dissolved in 56.8 ml of N, N-dimethylformamide, 5.83 g of 2-nitroiminoimidazolidine, namely the intermediate VI and 4.6 g of triethylamine are added, and the reaction solution reacts for 24 hours at 80 ℃. 70 ml of water and 100 ml of ethyl acetate are added to the reaction solution, the organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of ethyl acetate each time, the organic phases are combined and washed 3 times with saturated saline solution 120 ml each time, dried with anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain 5.44 g of white solid, namely the intermediate VIIa, with the yield being 66.2%.
(6) Synthesis of 5-hydroxy imidacloprid VIII
The reaction process is as follows:
dissolving 5.4 g of the intermediate VIIa in 162 ml of dichloromethane, adding 44.8 ml of 1 mol/L dichloromethane solution of boron trichloride at the temperature of-20 ℃, gradually returning to the temperature of 20 ℃ for reaction for 16 hours, filtering the reaction solution, washing the filtrate three times by using saturated ammonium chloride solution, wherein each time is 100 ml, drying an organic phase, and recrystallizing and purifying by using methanol to obtain 2.05 g of white solid, namely 5-hydroxypyralin VIII, wherein the yield is 50.6%, the liquid phase purity is 99.8184%, IR is shown in figure 1, NMR is shown in figure 2, HPLC is shown in figure 3, and MS is shown in figure 4.
Example 2
The synthesis method of the 5-hydroxy imidacloprid comprises the following steps:
(1) synthesis of intermediate II
The reaction process is as follows:
10 g of methyl 5-hydroxynicotinate is dissolved in 150 ml of N, N-dimethylformamide, 11.34 g of N-chlorosuccinimide is added, and the reaction solution is heated to 80 ℃ to react for 12 hours. After the reaction solution was cooled to 50 ℃, the solvent was removed by vacuum distillation using an oil pump, 150 ml of ethyl acetate and 100 ml of water were added, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate, 50 ml each time, the organic phases were combined, washed three times with saturated brine, 180 ml each time, dried over anhydrous sodium sulfate and then spin-dried, and purified by column chromatography to obtain 4.87 g of an oily substance, i.e., intermediate ii, i.e., intermediate iiib, with a yield of 39.8%.
(2) Synthesis of intermediate IVb
The reaction process is as follows:
4.8 g of intermediate II, intermediate IIIb, was dissolved in 72 ml of toluene, 51.2 ml of a 1 mol/l toluene solution of diisobutylaluminum hydride was added under ice-cooling, and then reacted at 20 ℃ for 8 hours. After quenching with saturated ammonium chloride solution in ice bath, suction filtration with celite pad, extraction of filtrate with ethyl acetate three times, 100 ml each time, combining organic phases, drying with anhydrous sodium sulfate, spin drying, and column chromatography purification to obtain 2.07 g of oily matter, namely intermediate ivb, with 50.7% yield.
(3) Synthesis of intermediate vb
The reaction process is as follows:
2 g of intermediate IVb were dissolved in 66 ml of dichloromethane, 3.73 g of thionyl chloride was added, and the reaction was carried out at 60 ℃ for 2 hours. After the reaction was concentrated, the pH was adjusted to 8 with saturated sodium bicarbonate in ice bath, extracted three times with 40 ml of dichloromethane each time, dried with organic phase and then spin-dried, purified by column chromatography to obtain 1.09g of oil, i.e. intermediate vb, with a yield of 48.8%.
(4) Synthesis of 5-hydroxy imidacloprid VIII
The reaction process is as follows:
1 g of intermediate vb is dissolved in 18 ml of N, N-dimethylacetamide, 1.61 g of 2-nitroiminoimidazolidine, namely intermediate VI and 1.56 g of sodium bicarbonate are added, and the reaction solution reacts at 60 ℃ for 72 hours. Adding 40 ml of water and 60 ml of ethyl acetate into the reaction solution, separating an organic phase, extracting an aqueous phase with ethyl acetate for 3 times, 30 ml each time, combining the organic phases, washing the organic phases with saturated saline solution for 3 times, 100 ml each time, drying the organic phases with anhydrous sodium sulfate, concentrating the organic phases, and purifying the organic phases by column chromatography to obtain 0.38 g of white solid, namely 5-hydroxy imidacloprid VIII, wherein the yield is 24.9 percent and the purity of the liquid phase is 99.0359 percent.
Example 3
The synthesis method of the 5-hydroxy imidacloprid comprises the following steps:
(1) synthesis of intermediate II
The reaction process is as follows:
30 g of methyl 5-hydroxynicotinate is dissolved in 720 ml of dichloroethane, chlorine is introduced at 25 ℃, and about 28 g of chlorine is introduced after 4 hours of reaction. After bubbling nitrogen gas in the system for 30 minutes, the reaction solution was concentrated to 200 ml, the pH was adjusted to 8 with saturated sodium bicarbonate under ice bath, the organic phase was separated, dried over anhydrous sodium sulfate and then spin-dried, and column chromatography purification was performed once to obtain 10.75 g of an oily substance, i.e., intermediate ii, with a yield of 29.2%.
(2) Synthesis of intermediate IIIc
The reaction process is as follows:
10.7 g of intermediate II was dissolved in 160 ml of N, N-dimethylformamide, and 2.74 g of sodium hydroxide and 17.81 g of methyl iodide were added to react at 40 ℃ for 6 hours. After cooling, the reaction was quenched with saturated ammonium chloride, extracted three times with 120 ml each time with ethyl acetate, the organic phases were combined and washed three times with 100 ml each time with saturated brine, the organic phase was dried and spin dried, and column chromatography purification was carried out once to obtain 7.61 g of an oil, i.e., intermediate iiic, in 66.2% yield.
(3) Synthesis of intermediate IVc
The reaction process is as follows:
7.5 g of intermediate IIIc are dissolved in 150 ml of tetrahydrofuran, 1 g of lithium aluminium hydride is slowly added in portions in ice bath and the reaction is gradually brought back to 25 ℃ for 3 hours. The reaction solution was again slowly added with 1 ml of water, 1 ml of 15% aqueous sodium hydroxide solution and 3 ml of water in sequence on an ice bath, then anhydrous sodium sulfate and 50 ml of tetrahydrofuran were added, and then stirred at room temperature for 1 hour, filtered with celite, and the filtrate was spin-dried to obtain 4.25 g of an oil, i.e., intermediate ivc, with a yield of 65.8%.
(4) Synthesis of intermediate vc
The reaction process is as follows:
4.2 g of the intermediate IVc was dissolved in 85 ml of chloroform, and 6.75 g of elemental iodine, 4.45 g of imidazole and 7.61 g of triphenylphosphine were added in this order, followed by a reaction at 40 ℃ for 16 hours. After quenching the reaction solution with 5% sodium thiosulfate, drying and spin-drying with anhydrous sodium sulfate, and purifying by column chromatography, 5.48 g of oily substance, namely the intermediate Vc, is obtained, and the yield is 79.9%.
(5) Synthesis of intermediate VIIc
The reaction process is as follows:
5.4 g of the intermediate Vc are dissolved in 108 ml of acetonitrile, 3.47 g of 2-nitroiminoimidazolidine, namely the intermediate VI, and 5.27 g of potassium carbonate are added, and the reaction solution reacts for 14 hours at 87 ℃. The reaction was cooled to room temperature and filtered, and the filtrate was spin-dried and purified by column chromatography to give 2.98 g of a white solid, intermediate VIIc, in 54.8% yield.
(6) Synthesis of 5-hydroxy imidacloprid VIII
The reaction process is as follows:
2.9 g of the intermediate VIIc is dissolved in 116 ml of dichloroethane, and 4.06 g of aluminum trichloride is added for reaction at 75 ℃ for 36 hours. After the reaction solution was filtered while hot, the filtrate was concentrated and purified by column chromatography to obtain 650 mg of a white solid, i.e., 5-hydroxypicolin VIII, with a yield of 23.6% and a liquid phase purity of 99.1528%.
Claims (10)
1. A synthetic method of imidacloprid metabolite 5-hydroxy imidacloprid is characterized by comprising the following steps:
(1) dissolving a compound I, namely 5-hydroxy methyl nicotinate in a solvent, and reacting with a chlorinating reagent to obtain a compound II;
(2) dissolving the compound II obtained in the step (1) in a solvent, and reacting with alkali and alkyl halide to obtain a compound III;
in the compound III, R is methyl, benzyl, allyl or hydrogen, and when R is hydrogen, the compound II is directly used for the next reaction without the reaction of the step;
(3) dissolving the compound III obtained in the step (2) in a solvent, adding a reducing agent, and reacting to obtain a compound IV;
(4) dissolving the compound IV obtained in the step (3) in a solvent, and halogenating with a halogenating reagent to obtain a compound V;
in the compound V, X is chlorine, bromine or iodine;
(5) dissolving the compound V obtained in the step (4) in a solvent, and reacting the compound V with a compound VI under an alkaline condition to obtain a compound VII;
when R is hydrogen, the compound VII is 5-hydroxy imidacloprid without the step (6);
(6) dissolving the compound VII obtained in the step (5) in an organic solvent, and reacting with a deprotection reagent to obtain a compound VIII, namely 5-hydroxy imidacloprid;
2. the method for synthesizing 5-hydroxy imidacloprid as claimed in claim 1, wherein in step (1), the solvent is N, N-dimethylformamide, water, dioxane or dichloroethane, and the chlorinating agent is chlorine gas, N-chlorosuccinimide or sodium hypochlorite.
3. The method for synthesizing 5-hydroxypicolin according to claim 1, wherein in step (2), the solvent is acetone, acetonitrile, N-dimethylformamide or N, N-dimethylacetamide, the base is potassium carbonate, cesium carbonate, triethylamine or sodium hydroxide, and the alkyl halide is methyl iodide, benzyl bromide, benzyl chloride or allyl bromide.
4. The method for synthesizing 5-hydroxy imidacloprid as claimed in claim 1, wherein in step (3), the solvent is tetrahydrofuran, toluene, methanol or diethyl ether, and the reducing agent is lithium borohydride, sodium borohydride, lithium aluminum hydride or diisobutyl aluminum hydride.
5. The method for synthesizing 5-hydroxy imidacloprid as claimed in claim 1, wherein in step (4), the solvent is chloroform, dioxane, tetrahydrofuran or dichloromethane, and the halogenating agent is thionyl chloride, N-bromosuccinimide, phosphorus tribromide or iodine.
6. The method for synthesizing 5-hydroxypicolin according to claim 1, wherein in step (5), the solvent is N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide or N, N-dimethylacetamide, and the base is potassium carbonate, cesium carbonate, sodium bicarbonate or triethylamine.
7. The method for synthesizing 5-hydroxy imidacloprid as claimed in claim 1, wherein in step (6), the organic solvent is dichloromethane, dichloroethane, dioxane or toluene, and the deprotection reagent is boron trichloride, boron tribromide, aluminum trichloride or palladium tetratriphenylphosphine.
8. The method for synthesizing 5-hydroxy imidacloprid as claimed in claim 1, wherein in the step (1), the volume ratio of the solvent to the compound I is 5-30: 1; the mol ratio of the chlorination reagent to the compound I is 1-4: 1; in the step (2), the volume ratio of the solvent to the compound II is 10-100: 1; the molar ratio of the alkali to the compound II is 1-6: 1; the molar ratio of the alkyl halide to the compound II is 1-3: 1.
9. the method for synthesizing 5-hydroxy imidacloprid according to claim 1, wherein in the step (3), the volume ratio of the solvent to the compound III is 5-80: 1, the molar ratio of the reducing agent to the compound III is 0.5-5: 1; in the step (4), the volume ratio of the solvent to the compound IV is 5-50: 1; the mass ratio or the molar ratio of the halogenating agent to the compound IV is 0.1-5: 1.
10. in the step (5), the volume ratio of the solvent to the compound V is 5-50: 1; the molar ratio of the compound VI to the compound V is 0.7-2.2: 1; the molar ratio of the alkali to the compound V is 1-4: 1; in the step (6), the volume ratio of the organic solvent to the compound VII is 5-50: 1, the molar ratio of the deprotection reagent to the compound VII is 0.1-5: 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110288077A1 (en) * | 2008-09-24 | 2011-11-24 | Schering Corporation | Compounds for the treatment of inflammatory diseases |
| WO2013163466A1 (en) * | 2012-04-25 | 2013-10-31 | Presidio Pharmaceuticals, Inc. | Inhibitors of hepatitis c virus |
| CN111362935A (en) * | 2020-04-26 | 2020-07-03 | 梯尔希（南京）药物研发有限公司 | Synthesis method of N-hydroxy tropisetron |
| CN111433206A (en) * | 2017-10-05 | 2020-07-17 | 葛兰素史克知识产权开发有限公司 | Compound (I) |
-
2021
- 2021-04-20 CN CN202110433568.2A patent/CN113173911A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110288077A1 (en) * | 2008-09-24 | 2011-11-24 | Schering Corporation | Compounds for the treatment of inflammatory diseases |
| WO2013163466A1 (en) * | 2012-04-25 | 2013-10-31 | Presidio Pharmaceuticals, Inc. | Inhibitors of hepatitis c virus |
| CN111433206A (en) * | 2017-10-05 | 2020-07-17 | 葛兰素史克知识产权开发有限公司 | Compound (I) |
| CN111362935A (en) * | 2020-04-26 | 2020-07-03 | 梯尔希（南京）药物研发有限公司 | Synthesis method of N-hydroxy tropisetron |
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| SHINZO KAGABU等: "Insecticidal activity of imidacloprid derivatives with an alkoxy group at the C5 position of the pyridine ring", 《J. PESTIC. SCI.》 * |
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Application publication date: 20210727 |